HIV makes three enzymes namely, Reverse Transcriptase (RT), Protease (PT) and Integrase (IN) like all retroviruses and these three enzymes were considered as effective targets for drug development. Currently people infected with HIV are treated with RT and PT inhibitors drug cocktail. Although these first and second-generation inhibitors are effective, the appearance of drug resistant mutants renders these drugs ineffective in reducing the viral load. A third generation of drugs targeting HIV IN enzyme appears to hold promise. IN was considered as a suitable drug target from the beginning. Integrase is one of many metalloenzymes that requires divalent metal ions (Mg 2v or Mn zv) for its catalytic activity. Several lines of evidence suggest that divalent metal ion (Mg 2v or Mn 2v) cofactor is coordinated by the catalytic triad residues of IN and mutagenesis of the metal binding residues inhibit IN function. All the integrase inhibitors studied thus far contain a metal binding motif such as catechols, 1,2-diols, beta-dicarbonyls (DKA), o-hydroxyacids, hydrazides, etc. Many of these inhibitors do not show anti-viral function and so far only two IN inhibitors are successfully developed. Based on several SAR studies, a reasonable pharmacophore model containing the following key elements in an IN inhibitor can be proposed: (a) a metal ion binding motif to sequester Mg or Mn ion from the catalytic site of the enzyme; and (b) one to three independent hydrophobic groups to anchor the inhibitor to the enzyme. The metal ion chelation concept is gaining momentum in the design and development of new generation of IN inhibitors. The objectives of the proposal are to synthesize rationally designed novel HIV IN inhibitors endowed with strong, multiple Mg 2v or Mn 2v chelating motifs. Specifically, we propose to prepare IN inhibitors of four molecular scaffolds 1-4, assess the efficacy of these novel compounds in inhibiting IN function, and to determine the effect of these inhibitors on HIV replication in cell culture. Preliminary results with a few analogs of these inhibitors show good anti-HIV property. These inhibitors form a new generation of IN inhibitors and will be useful in treating IN drug resistant viral mutants.